The immune system is our defense against a variety of antigens, including those associated with bacteria, viruses, and cancerous cells. However, not all immunological responses are beneficial. Allergic diseases including asthma, allergic rhinitis, and atopic dermatitis affect as much as 5 to 10% of the U.S. population. Asthma alone is estimated to affect more than 15 million Americans, with more than 5000 dying annually. More than 10% of children have allergic dermatitis at some point during their childhood (Leung, D., Mol. Gen. and Metab. 63:157–167 (1998). The prevalence of allergic diseases and their associated morbidity has risen dramatically over the last 20 years. Effective therapies that lack deleterious side effects for the management of these diseases are lacking.
Initiation of the immune response involves specific recognition of an antigenic molecule. The immune response is initiated following the binding of antigen to a specific cell receptor. There are a wide variety of receptors, including the T-cell antigen receptor (TCR), the B-cell antigen receptor (BCR), and receptors for the Fc portion of different immunoglobulin subclasses (FCR). One example of an FCR is FcεRI, which binds IgE.
Activation or inhibition of the immune response occurs at the receptor site and involves two different motifs: the immunoreceptor tyrosine-based activation motif (ITAM) and the immunoreceptor tyrosine-based inhibition motif (ITIM). The tyrosine-based motifs undergo rapid, but transient phosphorylation upon receptor ligation, thereby regulating key components of the signaling cascade. ITAMs activate an immune response, whereas the ITIMs inhibit it.
IgE is a well known mediator of the immediate-type hypersensitivity allergic reactions including, e.g., allergic rhinitis (“hay fever”), extrinsic asthma, and food and drug allergies. IgE is secreted by, and expressed on the surface of B-cells or B-lymphocytes. Upon exposure of a mammal to an allergen (antigen), the B-cells specific for that particular antigen are “activated” and develop into IgE-secreting plasma cells. The allergen-specific IgE circulates through the bloodstream. In IgE-mediated allergic reactions, IgE binds through its Fc portion to FcεRI receptors present on the surface of basophils, mast cells, and Langerhans cells. If the IgE bound to the surface of these cells then contacts and binds an allergen, this causes a cross-linking of the bound IgE molecules and hence the underlying receptors, and triggers the release of pharmacologic mediators, such as histamine, serotonin, leukotrienes and the slow-reacting substance of anaphylaxis. These mediators cause the pathologic manifestations of allergic reactions.
Many IgE-mediated allergic conditions or diseases could be inhibited or ameliorated if mast cell activation could be avoided. Cross-linking of an ITAM with an ITIM may cause such a negative regulation of mast cell activation. In fact, it has been demonstrated in animal models that cross-linking of IgE bound to FcεRI (ITAM) with a murine ITIM, gp49 (primarily expressed on the surface of mast cells), inhibits release of mast cell mediators of allergy. International Patent Application WO 98/09638 discusses a rat antibody that targets gp49 (designated mAb B23.1) on the surface of murine mast cells. It was demonstrated that coligation of the FcεRI and gp49 on the surface of mast cells suppresses FcεRI-mediated exocytosis, as evidenced by the release of the secretory granule mediator β-hexosaminidase and the generation of the membrane derived pro-inflammatory lipid mediator leukotriene (LT) C4.
The coligation in this International patent application was accomplished using an F(ab′)2 antibody fragment targeting the light chains of both the B23.1 antibody and rat IgE. The mast cells were primed with mAb B23.1 and rat IgE, and then the F(ab′)2 fragment was added. Inhibition of exocytosis as compared with controls was evident. This inhibitory effect is believed to be caused by inhibition of the signal transduction cascade that otherwise leads to the release of such mast cell mediators.
Inhibition of mast cell allergic mediators through cross-linking of FcεRI with gp49 (or the human equivalent, HM18) offers new potential treatments for IgE-mediated allergic diseases. Cross-linking of other ITIM and ITAM receptors, which could inhibit activation of a number of cell types carrying these receptors, could provide treatments for a number of diseases and conditions where cellular activation is a disease component, thus providing a much needed therapy for these diseases.